Co-crystal of nadifloxacin with oxalic acid

The nadifloxacin oxalic acid co-crystal is stabilized by intermolecular hydrogen bonds. FT–IR, DSC and XRD studies were carried out to confirm the structure and a Hirshfeld surface analysis was performed to investigate the intermolecular interactions.


Chemical context
A co-crystal is a multi-component molecular complex with a definite stoichiometric ratio of two compounds that can interact through hydrogen bonds, van der Waals forces, andstacking interactions to name just a few (Stahly 2009;Vishweshwar et al., 2006). The formation of multi-component crystals, i.e. salts and co-crystals through a crystal-engineering approach has been demonstrated to be a versatile tool to improve the physicochemical properties of APIs (active pharmaceutical ingredients) including solubility, dissolution rate, stability, tabletability, etc. (Mannava et al., 2021(Mannava et al., , 2022. Co-crystals can be synthesized by various methods such as solvent-assisted grinding, sonication and slow evaporation among others. Co-crystals of fluoroquinolone antibiotics with organic acids have been reported to exhibit higher solubility than the parent molecule (Reddy et al., 2011). Nadifloxacin fluoroquinolone (Kido & Hashimoto, 1994) is an antibiotic used for the treatment of commonly formed acne, acting against Staphylococcus aureus, Streptococcus spp., coagulasenegative staphylococci (CNS), Propionibacterium acnes, and Propionibacterium granulosum strains (Nenoff et al., 2004). It also shows antibacterial activity against skin infections (Kumar & Khatak, 2021). Here we report the structure of a cocrystal formed between nadifloxacin (NAD) and oxalic acid (OA), which is stabilized through intermolecular hydrogen bonds.

Structural commentary
The title co-crystal is shown in Fig. 1. The asymmetric unit is comprised of one NAD molecule in a general position and half of an OA molecule, located about a center of inversion, so the co-crystal is formulated as a 2:1 NAD:OA adduct. NAD is a non-planar molecule [C7-C6-N2-C5 = 104.0 (3) ]. The adduct forms through O6-H6Á Á ÁO4 hydrogen bonds (Table 1) and crystallizes in the triclinic crystal system in space group P1. An intramolecular O2-H2Á Á ÁO3 hydrogen bond is formed in the NAD molecule with an R 1 1 (6) ring motif of ( Fig. 1).

Figure 3
Two ribbons of NAD and OA formed by hydrogen bonds.

Figure 2
Packing of the title compound with hydrogen bonds depicted by dashed lines.

Figure 4
The ring motif between oxalic acid and nadifloxacin in the co-crystal.

Synthesis and crystallization
NAD was purchased from Swapnroop Drugs and Pharmaceuticals, India, and the remaining chemicals were purchased from Sigma-Aldrich, India. All chemicals and solvents were of analytical grade.
NAD (50 mg, 0.360 mmol) and OA (17 mg, 0.126 mmol) were dissolved in a mixed chloroform-acetone solvent (5 ml:5 ml), heated on a water bath for 15-20 min and then kept undisturbed for slow evaporation. Crystals were obtained at room temperature after 24-48 h. They were characterized by FTIR, DSC, and single crystal XRD.
Infrared spectra of NADÁOA crystals were recorded using FT-IR spectroscopy (Thermo-Nicolet 6700 FTIR-NIR spectrometer) with the samples made in KBr pellets. Omnic software (Thermo Scientific, Waltham, MA) was used to analyze the data. Each sample was scanned in the range 400-4000 cm À1 In the IR spectrum, the C O stretching frequencies for NAD (carboxylic acid group) and OA were observed at 1716 cm À1 and 1682 cm À1 , respectively, while in the co-crystal, the former now appears at 1734 cm À1 . Differential Scanning Calorimetric (DSC) analysis indicated the melting points of NAD and OA to be 478.9 K and 387.8 K, respectively, while the melting point of the co-crystal is 438.8 K.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2 Two-dimensional fingerprint plots and relative contribution of various interactions to the Hirshfeld surface of the NAD molecule.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq C1 0.7236 (